1. Field of the Invention
Morphine is a well known narcotic analgesic having the structural formula: ##STR2##
The compounds of this invention are structurally related to morphine and are named according to the morphinan system of nomenclature using the morphinan nucleus which is shown below: ##STR3## The numbering and stereochemical placement of atoms in the morphinan system is the same as that depicted for morphine. A dashed line is used to represent a covalent bond projecting below the plane of a reference atom while a wedged or heavily accented line signifies a covalent bond above such plane. The compounds of this invention have the same stereochemical placement of atoms as depicted for morphine unless otherwise indicated. In some structures, such as the general formula appearing on Page 1 hereof, a serpentine line (.about.) denotes orientation of a covalent bond either above or below the plane of reference.
Morphine and its structurally related relatives are used primarily as analgesics. While extremely effective for the relief of moderate to severe pain these compounds are narcotic and most possess dependence-inducing ability and produce other side effects such as emesis, constipation, sweating, respiratory depression and myosis which make them less than ideal analgesics. It is impossible to predict, based on structure alone, whether a particular morphine-like compound will act as an analgesic (agonist), a narcotic antagonist or possess a combination of these properties since very minute structural modifications in the molecule result in significant changes in pharmacological activity. A compound with the appropriate profile of analgesic (agonist) and narcotic antagonist actions has potential for treatment of moderate to severe pair without the liability of drug dependence or drug abuse. Those compounds which exhibit only agonist activity are, of course, useful as analgesics whereas those compounds which exhibit only antagonist activity find utility in the treatment of drug addiction.
Prior Art
Morphinans which are hydroxy substituted in the 14-position are known. Thus, I. J. Pachter reports in Narcotic Antagonists, Advances in Biochemical Psychopharmacology, Vol. 8, Raven Press, New York 1973, p. 57, the preparation of compounds having the structure: ##STR4## where R is cyclopropyl (A) or cyclobutyl (B). The compound in which R is cyclopropyl is reported to be essentially a narcotic antagonist while that compound in which R is cyclobutyl is reported to possess both analgesic and narcotic antagonist activity. This article also reports the preparation by the Shionogi Company in Japan of a compound having the formula: ##STR5## It is stated that this compound is very long acting and more potent than A (above), cyclazocine or naloxone. Naloxone is a potent narcotic antagonist whereas cyclazocine has mixed analgesic/narcotic antagonist activity.
Compounds of the general formula: ##STR6## where R is a hydrogen atom or hydroxyl group; R.sub.1 is allyl, .gamma.,.gamma.-dimethylallyl or cyclopropylmethyl; and F represents the presence or absence of a double bond are disclosed in U.S. Pat. No. 3,654,280 which issued Apr. 4, 1972.